Yersinia pestis is the causative agent of bubonic, septicemic and pneumonic plague and represents a serious bioterrorism threat. Most studies on Y. pestis pathogenesis have been directed at identifying and defining the function of the many virulence factors that enable this organism to subvert host defenses. In contrast, relatively few studies have directly examined those immune responses that might be critical for effective host defense against Y. pestis. This proposal takes an unbiased approach aimed at defining the mechanistic basis of resistance of BALB/cJ mice to infection by Y. pestis which appears to be mediated by the early defenses of phagocytes. The first aim of this proposal is to determine the genetic basis of resistance of BALB/cJ mice through classical forward genetic screening and fine mapping of the resistance locus called plague resistance locus 1 (prl1). This analysis will be coupled with phagocyte gene expression data from resistance and susceptible strains. The second aim of this proposal examines BALB/cJ macrophages and neutrophils in vitro for enhanced phagocytic and bactericidal activity as well as resistance to Y. pestis cytotoxicity and apoptosis. Aim 2 will also comparatively examine the bacterial burdens and viability of splenic macrophages and neutrophils at early time points following Y. pestis infection of resistant and susceptible mouse strains. The critical role of neutrophils in BALB/cJ resistance will be assessed though adoptive transfer of these innate immune cells from resistant prl1 strains to susceptible mice. The findings from these studies will not only lead to a better understanding of host defense against Y. pestis in rodent populations, which constitute the major environmental reservoir for this pathogen, but may be generally applicable toward understanding human immunity to this pathogen. The host defenses essential for resistance to Y. pestis are likely to be novel and could define early innate immune targets for therapeutic intervention following infection.